School of Chemistry and Chemical Engineering, Guangxi University, Nanning 530004, China.
Faculty of Chinese Medicine Science, Guangxi University of Chinese Medicine, Nanning 530004, China.
Bioorg Med Chem. 2018 Aug 7;26(14):4136-4144. doi: 10.1016/j.bmc.2018.07.001. Epub 2018 Jul 2.
Based on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC 5.7 µM and 8.5 µM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form π-π stacking interaction with DNA, leading to the improvement of biological activity. Its mode of action was to inhibit the activity of DNA Topo I, followed by the G0/G1 phase arrest. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound and 10b could emerge as promising lead compounds for the development of novel Topo I inhibitors.
基于我们之前的研究和喜树碱与 Topo I 的结合模式，设计、合成了一系列含有共轭平面结构的新型槐定碱亚胺衍生物，并对其体外抗癌活性进行了测试。结果表明，大多数衍生物表现出很强的活性。特别是化合物 10b 对 HepG-2 和 HeLa 细胞系的抑制增殖活性分别达到 IC 5.7µM 和 8.5µM，显示出优异的活性。分子对接研究表明，引入共轭平面结构可以与 DNA 形成π-π堆积相互作用，从而提高生物活性。其作用方式是抑制 DNA Topo I 的活性，随后使细胞停滞在 G0/G1 期。这项工作为这类化合物的结构优化和抗癌途径的探索提供了理论依据，化合物 10b 可能成为开发新型 Topo I 抑制剂的有前途的先导化合物。
